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EP1802577A1 - Amides d'indane possedant une activite antiproliferative - Google Patents

Amides d'indane possedant une activite antiproliferative

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Publication number
EP1802577A1
EP1802577A1 EP05851222A EP05851222A EP1802577A1 EP 1802577 A1 EP1802577 A1 EP 1802577A1 EP 05851222 A EP05851222 A EP 05851222A EP 05851222 A EP05851222 A EP 05851222A EP 1802577 A1 EP1802577 A1 EP 1802577A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
amino
represents hydrogen
compound
halo
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP05851222A
Other languages
German (de)
English (en)
Inventor
Yamin Wang
Tindy Li
Eric Mull
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Pharmaceuticals Corp
Original Assignee
Bayer Pharmaceuticals Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bayer Pharmaceuticals Corp filed Critical Bayer Pharmaceuticals Corp
Publication of EP1802577A1 publication Critical patent/EP1802577A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/48—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring being part of a condensed ring system of the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/40—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings
    • C07C271/56—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/26—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/30—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by halogen atoms, or by nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/32—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms
    • C07C275/34—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C07D209/16—Tryptamines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/65—One oxygen atom attached in position 3 or 5
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D277/82—Nitrogen atoms

Definitions

  • the invention relates to novel compounds and processes for their preparation and their use for preparing medicaments for the treatment of disorders, especially hyper- proliferative disorders.
  • the present invention provides a compound of formula (I)
  • A represents
  • n, p, q and r represent 0, 1, 2, or 3;
  • R 1 represents hydroxy, alkoxy, amino or alkylamino
  • R 2 represents hydrogen, alkyl or halo
  • R 3 represents hydrogen, alkyl or halo
  • R 4 represents hydrogen or alkyl
  • R 5 represents hydrogen, alkyl or halo
  • R 6 represents hydrogen
  • R 6 represents alkyl, wherein alkyl can be substituted with 0, 1 or 2 substituents selected from the group consisting of halo, hydroxy, alkoxy, amino and alkylamino; or
  • R 6 represents alkylcarbonyl
  • R 6 represents alkylaminocarbonyl
  • R 6 represents alkylsulfonyl
  • R 7 represents hydrogen or alkyl
  • R represents hydrogen or alkyl
  • R 9 represents hydrogen, alkyl, halo, hydroxy or alkoxy
  • R 10 represents hydrogen, alkyl, halo, hydroxy or alkoxy
  • R 1 ' represents hydrogen, phenyl, or benzthiazolyl
  • R 12 represents pyridyl, thiazolyl, or indolyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of alkyl, alkoxy and halo; or
  • R 12 represents phenyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of alkyl, alkoxy, halo and amino;
  • R 13 represents pyridyl or phenyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of alkyl, alkoxy and halo;
  • R 14 represents alkyl or phenyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of alkyl, alkoxy and halo;
  • R 15 represents hydrogen, pyridyl, pyridyloxy, phenoxy, or phenyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of alkyl, alkoxy and halo;
  • R 16 represents hydrogen or alkyl
  • X represents oxygen or sulfur
  • the compounds of this invention may contain one or more asymmetric centers, depending upon the location and nature of the various substituents desired.
  • Separated, pure or partially purified isomers or racemic mixtures of the compounds of this invention are also included within the scope of the present invention. The purification of said isomers and the separation of said isomeric mixtures can be accomplished by standard techniques known in the art.
  • the invention also relates to tautomers of the compounds, depending on the structure of the compounds.
  • Salts for the purposes of the invention are preferably pharmaceutically acceptable salts of the compounds according to the invention.
  • Pharmaceutically acceptable salts of the compounds (I) include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, for example salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
  • Pharmaceutically acceptable salts of the compounds (I) also include salts of customary bases, such as for example and preferably alkali metal salts (for example sodium and potassium salts, alkaline earth metal salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, such as illustratively and preferably ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, dihydroabietylamine, arginine, lysine, ethylenediamine and methylpiperidine.
  • alkali metal salts for example sodium and potassium salts, alkaline earth metal salts (for example calcium and magnesium salts)
  • Solvates for the purposes of the invention are those forms of the compounds that coordinate with solvent molecules to form a complex in the solid or liquid state.
  • Hydrates are a specific form of solvates, where the solvent is water.
  • Alkoxy represents a straight-chain or branched hydrocarbon radical having 1 to 6, or, in another embodiment, 1 to 4, or in yet another embodiment 1 to 3 carbon atoms and bound via an oxygen atom, illustratively representing methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, isopentoxy, hexoxy, isohexoxy.
  • alkoxy and “alkyloxy” are often used synonymously.
  • Alkylamino represents an alkylamino radical having one or two (independently selected) alkyl substituents, illustratively representing methylamino, ethylamino, n- propylamino, isopropylamino, tert-butylamino, n-pentylamino, n-hexylamino, TV 1 TV- dimethylamino, N,N-diethylamino, N-ethyl-N-methylamino, N-methyl-N- n-propylamino, N-isopropyl-N-n-propylamino, N-t-butyl-N-methylamino, N-ethyl-N- n-pentylamino and N-n-hexyl-N-methylamino.
  • Alkylaminocarbonyl represents an alkylaminocarbonyl radical having one or two
  • alkyl substituents illustratively representing methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylamino- carbonyl, tert-butylaminocarbonyl, n-pentylaminocarbonyl.
  • n-hexylaminocarbonyl N,N-dimethylaminocarbonyl, N,N-diethylaminocarbonyl, N-ethyl-N- methylaminocarbonyl, N-methyl-/V-n-propylaminocarbonyl, N-isopropyl-N-n- propylaminocarbonyl, N-t-butyl-N-methylaminocarbonyl, N-ethyl-N-n-pentylamino- carbonyl and N-n-hexyl-N-methylaminocarbonyl.
  • Alkylcarbonyl represents an carbonyl radical having one alkyl substituent, illustratively representing methylcarbonyl or ethylcarbonyl.
  • Alkylsulfonyl represents *-S(O) 2 alkyl, illustratively representing methylsulfonyl or ethylsulfonly.
  • Halo represents fluorine, chlorine, bromine or iodine.
  • a * symbol next to a bond or line through a bond denotes the point of attachment in the molecule.
  • chemically unstable compounds are excluded in the context of the present invention.
  • a chemically unstable compound would be one where two nitrogen or oxygen substituents are bonded to a single aliphatic carbon atom.
  • Another example of a chemically unstable compound would be one where an alkoxy group is bonded to the unsaturated carbon of an alkene to form an enol ether.
  • an aliphatic carbon atom attached to oxygen may not also bear a chloro, bromo or iodo substituent, and when any alkyl group is attached to O, S, or ⁇ , and bears a hydroxyl substituent, then the hydroxyl substituent is separated by at least two carbon atoms from the O, S, or N to which the alkyl group is attached.
  • the present invention provides a compound of formula (I), wherein A represents
  • the present invention provides a compound of formula (I), wherein A represents
  • the present invention provides a compound of formula (I), wherein
  • R 1 represents hydroxy or amino
  • R 2 represents hydrogen
  • R 3 represents hydrogen
  • R 4 represents hydrogen; R represents hydrogen;
  • R 6 represents hydrogen
  • R 6 represents alkyl
  • the present invention provides a compound of formula (H)
  • R 1 represents hydroxy, alkoxy, amino or alkylamino
  • R represents hydrogen, alkyl or halo
  • R 3 represents hydrogen, alkyl or halo
  • R 4 represents hydrogen or alkyl
  • R 5 represents hydrogen, alkyl or halo
  • R represents hydrogen; or R 6 represents alkyl, wherein alkyl can be substituted with 0, 1 or 2 substituents selected from the group consisting of halo, hydroxy, alkoxy, amino and alkylamino; or
  • R 6 represents alkyl carbonyl
  • R 6 represents alkylaminocarbonyl
  • R 6 represents alkylsulfonyl
  • R 7 represents hydrogen, alkyl, methoxymethyl or methoxyethyl
  • R represents hydrogen or alkyl
  • R 9 represents hydrogen, alkyl, halo, hydroxy or alkoxy
  • R 10 represents hydrogen, alkyl, halo, hydroxy or alkoxy
  • the present invention provides a compound of formula (II), wherein
  • R 1 represents hydroxy or amino
  • R 2 represents hydrogen, alkyl or halo
  • R 3 represents hydrogen
  • R 4 represents hydrogen
  • R 5 represents hydrogen
  • R 6 represents hydrogen
  • R 6 represents alkyl, wherein alkyl can be substituted with 0, 1 or 2 substituents selected from the group consisting of halo, hydroxy, alkoxy, amino and alkylamino; or
  • R 6 represents alkylcarbonyl
  • R 6 represents alkylaminocarbonyl
  • R 6 represents alkylsulfonyl
  • R 7 represents hydrogen
  • R 8 represents hydrogen
  • R 9 represents hydrogen
  • R 10 represents hydrogen
  • the present invention provides a compound of formula (II), wherein R 6 is not hydrogen.
  • the present invention provides a compound of formula (II), wherein R 1 is alkylamino having one alkyl substituent.
  • the present invention provides a compound of formula (II), wherein R 1 is amino.
  • the compounds used in this invention may be prepared by standard techniques known in the art, by known processes analogous thereto, and/or by the processes described herein, using starting materials which are either commercially available or producible according to routine, conventional chemical methods.
  • the particular process to be utilized in the preparation of the compounds of this invention depends upon the specific compound desired. Such factors as whether the amine is substituted or not, the selection of the specific substituents possible at various locations on the molecule, and the like, each play a role in the path to be followed in the preparation of the specific compounds of this invention. Those factors are readily recognized by one of ordinary skill in the art.
  • connection A may be constructed by forming connection A, or connections A and B, described further below.
  • connection C may be constructed by forming connection C.
  • Connection A is the carbonylation of the optionally substituted indane portion of the molecule.
  • Connection B is the formation of amide between the optionally substituted propenoate and the optionally substituted aniline. It could be achieved by two routes outlined in Flow diagram II.
  • Connection C can be formed via the reductive amination of optionally substituted indanones or a reduction followed by further manipulation as illustrated in Flow Diagram III.
  • the optionally substituted tryptamines are either commercially available or are prepared in similar manners as described in the literature procedures (for example, Tetrahedron Letters (2004), 45(15), 3123-3126; Journal of Medicinal Chemsitry, (1998), 41, 3831-3844; and Bioorganic & Medicinal Chemistry Letters (2003), 13, 1301-1305).
  • the compounds according to the invention exhibit useful pharmacological and pharmacokinetic properties. They are therefore suitable for use as medicaments for the treatment of disorders in humans and animals.
  • the compounds according to the invention are, because of their pharmacological properties, useful alone or in combination with other active components for treating or preventing hyper-proliferative disorders.
  • Another embodiment of the present invention relates to a method of using the compounds described above, including salts thereof and corresponding compositions thereof, to treat mammalian hyper-proliferative disorders.
  • This method comprises administering to a patient an amount of a compound of this invention, or a pharmaceutically acceptable salt thereof, which is effective to treat the patient's hyper-proliferative disorder.
  • a patient for the purpose of this invention, is a mammal, including a human, in need of treatment for a particular hyper-proliferative disorder.
  • Hyper-proliferative disorders include but are not limited to solid tumors, such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases. Those disorders also include lymphomas, sarcomas, and leukemias.
  • breast cancer examples include, but are not limited to invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.
  • cancers of the respiratory tract include, but are not limited to small-cell and non-small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma.
  • brain cancers include, but are not limited to brain stem and hypophtalmic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumor.
  • Tumors of the male reproductive organs include, but are not limited to prostate and testicular cancer.
  • Tumors of the female reproductive organs include, but are not limited to endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus.
  • Tumors of the digestive tract include, but are not limited to anal, colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal, small-intestine, and salivary gland cancers.
  • Tumors of the urinary tract include, but are not limited to bladder, penile, kidney, renal pelvis, ureter, and urethral cancers.
  • Eye cancers include, but are not limited to intraocular melanoma and retinoblastoma.
  • liver cancers include, but are not limited to hepatocellular carcinoma (liver cell carcinomas with or without f ⁇ brolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.
  • Skin cancers include, but are not limited to squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.
  • Head-and-neck cancers include, but are not limited to laryngeal / hypopharyngeal / nasopharyngeal / oropharyngeal cancer, and lip and oral cavity cancer.
  • Lymphomas include, but are not limited to AIDS-related lymphoma, non- Hodgkin's lymphoma, cutaneous T-cell lymphoma, Hodgkin's disease, and lymphoma of the central nervous system.
  • Sarcomas include, but are not limited to sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.
  • Leukemias include, but are not limited to acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.
  • the present invention provides a medicament containing at least one compound according to the invention.
  • the present invention provides a medicament containing at least one compound according to the invention together with one or more pharmacologically safe excipient or carrier substances, and also their use for the abovementioned purposes.
  • the active compound can act systemically and/or locally. For this purpose it can be administered in a suitable manner, such as for example by oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, ophtalmic or otic administration or in the form of an implant or stent.
  • the active compound can be administered in forms suitable for these modes of administration.
  • Suitable forms of oral administration are those according to the prior art which function by releasing the active compound rapidly and/or in a modified or controlled manner and which contain the active compound in a crystalline and/or amorphous and/or dissolved form, such as for example tablets (which are uncoated or coated, for example with enteric coatings or coatings which dissolve after a delay in time or insoluble coatings which control the release of the active compound), tablets or films/wafers which disintegrate rapidly in the oral cavity or films/lyophilisates, capsules (e.g. hard or soft gelatin capsules), dragees, pellets, powders, emulsions, suspensions and solutions.
  • tablets which are uncoated or coated, for example with enteric coatings or coatings which dissolve after a delay in time or insoluble coatings which control the release of the active compound
  • tablets or films/wafers which disintegrate rapidly in the oral cavity or films/lyophilisates
  • capsules e.g. hard or soft gelatin capsules
  • Parenteral administration can be carried out by avoiding an absorption step (e.g. by intravenous, intraarterial, intracardial, intraspinal or intralumbar administration) or by including absorption (e.g. by intramuscular, subcutaneous, intracutaneous or intraperitoneal administration).
  • Suitable parenteral administration forms are for example injection and infusion formulations in the form of solutions, suspensions, emulsions, lyophilisates and sterile powders.
  • Such parenteral pharmaceutical compositions are described in Part 8, Chapter 84 of Remington's Pharmaceutical Sciences, 18 th ed. 1990, Mack Publishing Group, Enolo.
  • Suitable forms of administration for the other modes of administration are for example inhalation devices (such as for example powder inhalers, nebulizers), nasal drops, solutions and sprays; tablets or films/wafers for lingual, sublingual or buccal administration or capsules, suppositories, ear and eye preparations, vaginal capsules, aqueous suspensions (lotions or shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems, milky lotions, pastes, foams, dusting powders, implants or stents.
  • inhalation devices such as for example powder inhalers, nebulizers
  • nasal drops solutions and sprays
  • tablets or films/wafers for lingual, sublingual or buccal administration or capsules, suppositories, ear and eye preparations, vaginal capsules, aqueous suspensions (lotions or shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems, milky lotion
  • the active compounds can be converted into the abovementioned forms of administration in a manner known to the skilled man and in accordance with the prior art using inert, non-toxic, pharmaceutically suitable auxiliaries.
  • the latter include for example excipients (e.g. microcrystalline cellulose, lactose, mannitol, etc.), solvents (e.g. liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (e.g. sodium dodecyl sulfate, polyoxysorbitan oleate etc.), binders (e.g. polyvinyl pyrrolidone), synthetic and/or natural polymers (e.g. albumin), stabilizers (e.g. antioxidants, such as, for example, ascorbic acid), dyes (e.g. inorganic pigments such as iron oxides) or taste- and/or odour-corrective agents.
  • excipients e.g. microcrystalline cellulose, lactose, manni
  • the total amount of the active ingredient to be administered will generally range from about 0.01 mg/kg to about 200 mg/kg, and preferably from about 0.1 mg/kg to about 20 mg/kg body weight per day.
  • a unit dosage may contain from about 0.5 mg to about 1500 mg of active ingredient, and can be administered one or more times per day.
  • the daily dosage for administration by injection including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily.
  • the transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/kg.
  • the daily inhalation dosage regimen will preferably be from 0.01 to 100 mg/kg of total body weight.
  • the compounds according to the invention are preferably isolated in more or less pure form, that is more or less free from residues from the synthetic procedure.
  • the degree of purity can be determined by methods known to the chemist or pharmacist (see Remington's Pharmaceutical Sciences, 18 th ed. 1990, Mack Publishing Group, Enolo).
  • the compounds are greater than
  • HPLC - electrospray mass spectra were obtained using a Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector set at 254 nm, a YMC pro C- 18 column (2 x 23 mm, 120A), and a Finnigan LCQ ion trap mass spectrometer with electrospray ionization. Spectra were scanned from 120-1200 amu using a variable ion time according to the number of ions in the source. The eluents were A: 2% acetonitrile in water with 0.02% TFA and B: 2% water in acetonirile with 0.018% TFA. Gradient elution from 10% B to 95% over 3.5 minutes at a flowrate of 1.0 mL/min was used with an initial hold of 0.5 minutes and a final hold at 95% B of 0.5 minutes. Total run time was 6.5 minutes.
  • Step 1 preparation of intermediate A, ethyl l-oxoindane-5-carboxylate
  • Step 2 preparation of intermediate B, ( ⁇ )-ethyl l- ⁇ [2-(1H-indol-3- yl)ethyl]amino ⁇ indane-5-carboxylate, hydrochloride salt
  • Step 3 preparation of intermediate C, ( ⁇ )-ethyl l- ⁇ (2- ⁇ [tert- butyl(dimethyl)silyl]oxy ⁇ ethyl)[2-(1H-indol-3-yl)ethyl]amino ⁇ indane-5-carboxylate
  • Step 4 preparation of Intermediate D, (+)-Ethyl l- ⁇ (2-hydroxyethyl)[2-(1H-indol-3- yl)ethyl]amino ⁇ indane-5-carboxylate
  • Step 5 preparation of intermediate E, ( ⁇ )-l- ⁇ (2-hydroxyethyl)[2-(1H-indol-3- yl)ethyl]amino ⁇ indane-5-carboxylic acid, hydrochloride salt
  • Step 6 preparation of compound example 2, (+)-N-(2-aminophenyl)-l- ⁇ (2- hydroxyethyl)[2-(1H-indol-3-yl)ethyl]amino ⁇ indane-5-carboxamide
  • Step 1 preparation of intermediate F, ( ⁇ )-ethyl l- ⁇ acetyl[2-(1H-indol-3- yl)ethyl]amino ⁇ indane-5-carboxylate
  • Step 2 preparation of intermediate G, ( ⁇ )-l- ⁇ acetyl[2-(1H-indol-3- yl)ethyl]amino ⁇ indane-5-carboxylic acid
  • Step 1 preparation of intermediate H, ( ⁇ )-ethyl l- ⁇ [(ethylamino)carbonyl][2-(1H- indol-3-yl)ethyl]amino ⁇ indane-5-carboxylate
  • Step 2 preparation of intermediate I, ( ⁇ )-l- ⁇ [(ethylamino)carbonyl][2-(1H-indol-3- yl)ethyl]amino ⁇ indane-5-carboxylic acid
  • Step 1 preparation of intermediate J, ( ⁇ )-ethyl l-[[2-(1H-indol-3- yl)ethyl] (methylsulfonyl)amino] indane-5 -carboxylate
  • Step 2 preparation of intermediate K, ( ⁇ )-l-[[2-(1H-indol-3- yl)ethyl](methylsulfonyl)amino]indane-5-carboxylic acid
  • Step 1 preparation of intermediate L, tert-buty ⁇ (2-aminophenyl)carbamate
  • Step 2 preparation of intermediate M, tert-butyl (2- ⁇ [(l-oxo-2,3-dihydro-1H-inden- 5 -yl)carbonyl ] amino ⁇ phenyl)carbamate
  • Step 3 preparation of intermediate N, ( ⁇ )-tert-butyl (2- ⁇ [(l- ⁇ [2-(1H-indol-3- yl)ethyl] amino ⁇ -2,3-dihydro- 1 H-inden-5-yl)carbonyl]amino ⁇ phenyl)carbamate
  • Step 4 preparation of intermediate O, ( ⁇ )-tert-butyl (2- ⁇ [(l- ⁇ ethyl[2-(1H-indol-3- yl)ethyl]amino ⁇ -2,3-dihydro- 1 H-inden-5 -yl)carbonyl] amino ⁇ phenyl)carbamate
  • the reaction was performed similarly as described in step 3 under compound example 2: LC/MS [M+l] 539.2, RT 2.93 min.
  • Step 1 preparation of intermediate P, tert-buty ⁇ [2-( ⁇ [(lZ)-l-(hydroxyimino)-2,3- dihydro-1H-inden-5-yl]carbonyl ⁇ amino)phenyl]carbamate
  • Step 2 preparation of intermediate Q, ( ⁇ )-tert-butyl (2- ⁇ [(l-amino-2,3-dihydro-1H- inden-5-yl)carbonyl]amino ⁇ phenyl)carbamate
  • a 3-neck flask was flushed with nitrogen and palladium on activated carbon (Degussa type) (3.36 g) was added. While under a positive flow of N 2 , 20 mL of MeOH was added to the flask.
  • Step 3 preparation of intermediate R, ( ⁇ )-pyridin-3-ylmethyl ⁇ 5-[( ⁇ 2-[(tert- butoxycarbonyl)amino]phenyl ⁇ amino)carbonyl]-2,3-dihydro-l H-inden-1 - yl ⁇ carbamate
  • CDI (3.18 g, 19.6 mmol) was dissolved in THF (5 mL) and cooled to 0°C. 3- pyridylcarbinol (2.14 g, 19.6 mmol) was diluted with THF (5 mL) then added dropwise to the stirring solution of CDI.
  • Step 1 preparation of intermediate S, ( ⁇ )-tert-butyl [2-( ⁇ [l-(ethylamino)-2,3- dihydro-1H-inden-5-yl]carbonyl ⁇ amino)phenyl]carbamate
  • Step 2 preparation of intermediate T, ( ⁇ )-tert-butyl [2-( ⁇ [l-(ethyl ⁇ [(2- phenylethyl)amino]carbonyl ⁇ amino)-2,3-dihydro-1H-inden-5- yl]carbonyl ⁇ amino)phenyl]carbamate
  • Step 1 preparation of intermediate U, ( ⁇ )-tert-butyl ⁇ 2-[( ⁇ l- [ethyl(phenylsulfonyl)amino]-2,3-dihydro- 1 H-inden-5- yl ⁇ carbonyl)amino]phenyl ⁇ carbamate
  • Step 2 preparation of compound example 20.
  • Step 1 preparation of intermediate V, ( ⁇ )-tert-buty ⁇ ⁇ 2-[( ⁇ l-[acetyl(ethyl)amino]- 2,3-dihydro-1H-inden-5-yl ⁇ carbonyl)amino]phenyl ⁇ carbamate
  • Step 2 preparation of compound example 25.
  • Step 1 preparation of intermediate W, 4-fluorophenyl ⁇ 5-[( ⁇ 2-[(tert- butoxycarbonyl)amino]phenyl ⁇ amino)carbonyl]-2,3-dihydro- 1 H-inden- 1 - yl ⁇ ethylcarbamate
  • Step 1 preparation of intermediate X, ( ⁇ )- ⁇ er/-butyl (2- ⁇ [(l- ⁇ [(2- methoxyphenyl)sulfonyl]amino ⁇ -2,3- dihydro- 1 H-inden-5-yl)carbonyl]amino ⁇ phenyl)carbamate
  • Step 1 preparation of intermediate Y, ( ⁇ )-tert-butyl ⁇ 2-[( ⁇ l-[(1H-imidazol-l- ylcarbonyl)amino] -2,3 -dihydro- 1 H-inden-5 -yl ⁇ carbonyl)amino]phenyl ⁇ carbamate
  • CDI (980 mg, 6.1 mmol) was suspended in THF (5 mL) and the mixture was cooled to 0°C. A solution of intermediate Q (2.0 g, 5.4 mmol) in THF (5 mL) was added dropwise to the stirring CDI. After 30 min, water and CH 2 Cl 2 were added to the reaction. The organic layer was collected, dried over Na 2 SO 4 , and concentrated.
  • Step 2 preparation of intermediate Z, ( ⁇ )-tert-buty ⁇ [2-( ⁇ [l-( ⁇ [(pyridin-4- ylmethyl)am i no] carbonyl ⁇ amino)-2 , 3 -dihydro- 1 H-inden- 5 - yl]carbonyl ⁇ amino)phenyl]carbamate.
  • Step 1 preparation of intermediate AA, phenyl ⁇ 5-[( ⁇ 2-[(tert- butoxycarbonyl)amino]phenyl ⁇ amino)carbonyl]-2,3-dihydro- 1 H-inden- 1 - yl ⁇ carbamate
  • Step 1 preparation of intermediate AB, ( ⁇ )-tert-butyl [2-( ⁇ [l-(acetylamino)-2,3- dihydro-1H-inden-5-yl]carbonyl ⁇ amino)phenyl]carbamate
  • Step 1 preparation of intermediate AC, 3-phenylpropyl ⁇ 5-[( ⁇ 2-[(tert- butoxycarbonyl)amino]phenyl ⁇ amino) carbonyl]-2,3-dihydro- 1 H-inden- 1 - yl ⁇ carbamate
  • Step 2 preparation of compound example 57.
  • the reaction was performed similarly as described in step 5 under compound example 6.
  • 1 H-NMR (DMSO-d6) ⁇ 9.59 (s, 1H), 7.76-7.83 (m, 3H), 7.65 (d, 1H), 7.24-7.31 (m, 3H), 7.11-7.22 (m, 4H), 6.92- 6.96 (ddd, 1H), 6.74-6.77 (dd, 1H), 6.55-6.60 (ddd, 1H), 5.06 (q, 1H), 4.87 (s, 2H), 4.00 (t, 2H), 2.92-3.01 (m, 1H), 2.78-2.87 (m, 1H), 2.66 (t, 2H),. 2.38-2.47 (m, 1H), 1.77-1.93 (m, 3H).
  • Step 1 preparation of intermediate AD, ( ⁇ )-tert-butyl ⁇ 2-[( ⁇ l- [(anilinocarbonothioyl)amino]-2,3-dihydro- 1 H-inden-5- yl ⁇ carbonyl)amino]phenyl ⁇ carbamate
  • Step 1 preparation of intermediate AE, ( ⁇ )-tert-butyl [2-( ⁇ [l-(l ,3-benzothiazol-2- ylamino)-2,3-dihydro-1H-inden-5-yl]carbonyl ⁇ amino)phenyl]carbamate
  • Step 2 preparation of compound example 1 14.
  • the reaction was performed similarly as described in step 5 under example 6.
  • 1 H-NMR (DMSO-d6) ⁇ 9.61 (s, 1H), 8.45 (d, 1H), 7.87 (s, 1H), 7.78 (d, 1H), 7.66-7.69 (dd, 1H), 7.34-7.44 (m, 2H), 7.20-7.25 (ddd, 1H), 7.14 (d, 1H), 7.00-7.05 (ddd, 1H), 6.92-6.96 (ddd, 1H), 6.74-6.77 (dd, 1H), 6.55-6.60 (ddd, 1H), 5.53 (q, 1H), 3.00-3.09 (m, 1H), 2.88-2.96 (m, 1H), 2.59- 2.66 (m, 1H), 1.92-2.01 (m, 1H).
  • Step 1 preparation of intermediate AF, tert-butyl ⁇ 2-[( ⁇ l-[(3-pyridin-3- ylpropanoyl)amino]-2,3-dihydro-1H-inden-5-yl ⁇ carbonyl)amino]phenyl ⁇ carbamate
  • Step 2 preparation of compound example 122
  • Step 1 preparation of intermediate AG, ( ⁇ )-tert-butyl (2- ⁇ [(l- ⁇ [(pyridin-3- yloxy)acetyl]amino ⁇ -2,3-dihydro- 1 H-inden-5-yl)carbonyl]amino ⁇ phenyl)carbamate
  • Step 2 preparation of compound example 123
  • the adherent tumor cell proliferation assay used to test the compounds of the present invention involves a readout called Cell Titre-Glo developed by Promega
  • HCTl 16 cells colon carcinoma, purchased from ATCC
  • test compounds were added over a final concentration range of 10 nM to 20 ⁇ M in serial dilutions at a final DMSO concentration of 0.2 %.
  • Cells were incubated for 72 h at 37 °C in complete growth media after addition of the test compound.
  • the cells are lysed and 100 microliters of substrate/buffer mixture is added to each well, mixed and incubated at room temperature for 8 min. The samples were read on a luminometer to measure the amount of ATP present in the cell lysates from each well, which corresponds to the number of viable cells in that well. Values read at 24 h incubation were subtracted as
  • Representative compounds of this invention showed a significant inhibition of tumor cell proliferation in the assays with HCTl 16 cells (> 50% inhibition at 10 uM).
  • the compounds according to the invention can be converted into pharmaceutical preparations as follows:
  • Example 1 100 mg of the compound of Example 1, 50 mg of lactose (monohydrate), 50 mg of maize starch (native), 10 mg of polyvinylpyrrolidone (PVP 25) (from BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.
  • the mixture of active component, lactose and starch is granulated with a 5% solution (m/m) of the PVP in water. After drying, the granules are mixed with magnesium stearate for 5 min. This mixture is moulded using a customary tablet press (tablet format, see above). The moulding force applied is typically 15 kN.
  • composition for oral administration: Composition:
  • Rhodigel xanthan gum from FMC, Pennsylvania, USA
  • 99 g of water 99 g of water
  • a single dose of 100 mg of the compound according to the invention is provided by
  • Rhodigel is suspended in ethanol and the active component is added to the suspension.
  • the water is added with stirring. Stirring is continued for about 6h until the swelling of the Rhodigel is complete.

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Abstract

L'invention concerne de nouveaux composés, leurs procédés de préparation, ainsi que leur utilisation dans la préparation de médicaments destinés à traiter certains troubles, tels que les troubles hyperprolifératifs.
EP05851222A 2004-10-15 2005-10-14 Amides d'indane possedant une activite antiproliferative Withdrawn EP1802577A1 (fr)

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